FRAGILE X SYNDROME A change or mutation in a gene on the X chromosome causes the fragile X syndrome.

It is the most common inherited cause of mental impairment. The syndrome occurs in approximately 1 in 3600 males and 1 in 4000 to 6000 females. Genes are given names to identify them and the gene responsible for Fragile X Syndrome is called the FMR-1 (fragile X mental retardation 1) gene. The mutation is in the DNA (the chemical that makes up genes). The specific location is given as Xq27.3. This means that it is on the X chromosome, in its long arm (q) and it is at the far end (27.3) The location of the mutation that sets in motion the Fragile X Syndrome is near the beginning of the FMR1 gene. The gene appears in three forms that are defined by the number of repeats of a pattern of DNA called CGG repeats, and at this location, there is normally a series of about 30 repeats of CGG. Individuals with less than 60 CGG repeats have a normal gene. Individuals with 50-230 CGG repeats have a premutation which means they carry an unstable mutation which can expand in future generations. Individuals with over 200 repeats have a full mutation which causes fragile X syndrome. The full mutation causes the gene to shut down or methylate a region of the FMR-1 gene. Normally, the FMR-1 gene produces an important protein called FMRP. When the gene is turned off, the individual does not make fragile X mental retardation protein (FMRP). The lack of this specific protein causes fragile X syndrome. Fragile X is inherited. Carrier men (transmitting males) pass the premutation to all their daughters but none of their sons. Each child of a carrier woman has a 50% chance of inheriting the gene. The fragile X premutation can be passed silently down through generations in a family before a child is affected by the syndrome. CLINICAL FEATURES SYNDROME OF FRAGILE X Physical Features: Enlarged ears, long face with prominent chin and large testicles (macro orchidism) Connective tissue problems includes: ear infections, mitral valve prolapse, flat feet, doublejointed fingers, hyperflexible joints, and other skeletal problems. Prepubertal Birth weight at the approximately 70th percentile Height: mostly between 50th and 70th percentile Head circumference: slightly increased Developmental Delay: Sits alone at 10th month, walks at 20.6 months, first meaningful words at 20 months. Behavioral Characteristics: In males: Attention Deficit Disorder, speech disturbances, hand biting, hand flapping and other mannerisms, excessive shyness, tantrums, autism, poor eye contact, and unusual responses to visual, auditory and pressure stimuli, hyperactivity. Postpubertal Mental Retardation Craniofacial features: prominent forehead, prominent jaw, large prominent ears, long face. Macro orchidism (enlarged testes) Additional Features: Orthopedic: joint hypersensitivity, torticollis (a contracted state of the neck Kyphoscoliosis (backward and lateral cuvature of the spinal column) Opthalmologic: myopia and strabismus Dermatologic: fine velvety skin with striae Genitourinary cryptochidism ( failure of the testes to descend into the scrotum) and inguinal hernia

Epilepsy, gynecomastia development of mammary glands)

hyperflexia, (excessive the male

Females with fragile X syndrome may share some of the physical features seen in males but usually to a lesser degree. In addition, Fragile X has an impact on the menstrual cycle in some carrier females. IMPORTANCE OF KNOWING MOLECULAR BASIS OF FRAGILE X THE

and thus the conditions may occur more frequently or severely in subsequent generations. These conditions are often caused by a gene change that begins with a premutation and then expands to a full mutation in subsequent generations. Premutations are defined as having 60-200 CGG repeats and can occur in both males and females. In males it usually does not expand to a full mutation when passed on to his daughters (A male carrier never passes on the fragile X gene to his sons as he passes on his Y chromosome to his son. A female with the premutation will often pass on a larger version of the mutation to her children. As the size of the premutation increases, there is an increased possibility that a child will receive the full mutation. Typically, the premutation has no observable impact. However, some females with a premutation will experience early menopause. (POF) Additionally, some older adults with premutations may develop a neurological condition called FXTAS (often misdiagnosed as a "Parkinson's-like" condition). Approximately 1 in 250 females and 1 in 800 males carry the premutation. A full mutation is defined as having over 200 CGG repeats on the southern blot DNA test. In addition, most full mutation genes have some degree of methylation (the process which "turns off" the gene). Males with a full mutation usually have fragile X syndrome, though there is a small percentage of males with a full mutation who do not have mental retardation. About 30% of females with a full mutation have no cognitive deficits. The remaining 65-70% of females with a full mutation will have some difficulties with cognitive, behavioral, or social functioning and may have some of the physical features found in males. INHERITANCE Fragile X in an "X-linked" condition, which means that the gene is on the X chromosome. Since a woman has two X chromosomes a woman with a premutation or full mutation has a 50% chance of passing on the X with the mutation in each pregnancy. If she has a premutation, and it is passed on (to either males or females), it can

It is important for the medical personnel and for scientists to understand the molecular basis of Fragile X syndrome in order for the attending physician to be able to explain to family members, the condition of the patient. Fragile X Syndrome worsens in each succeeding generation. Knowledge of the genetic basis of the disease can help enlighten the family, so that chromosomal analysis can be performed. MOLECULAR DIAGNOSIS During the 1970's and 1980's the test available for diagnosing fragile X syndrome was the chromosomal or cytogenetic test. While it was helpful, it was not always accurate. In the 1990's, two molecular DNA tests became available. These are: The Southern Blot analysis -this determines if the gene has a full mutation and its approximate size, if the gene has been methylated and if there is mosaicism (a mixture of different cell types). The polymerase chain reaction (PCR) analysis can determine the actual number of repeats in individuals with a normal size gene or with a premutation. It is not the test of choice to diagnose a full mutation, but is quite accurate in determining premutation and normal gene repeat numbers. Fragile X syndrome is one of a group of conditions called trinucleotide repeat disorders. A common feature of these conditions is that the gene can change sizes over generations, becoming more unstable,

remain a premutation or it can expand to a full mutation. If she has a full mutation and it is passed on (to either males or females), it will remain a full mutation. In many X linked conditions only males who inherit the abnormal gene are affected, however in fragile X syndrome females can also be affected. Additionally, in other X linked conditions all males who carry the gene are affected, however in fragile X syndrome, unaffected males can carry the gene in the premutation form and have no symptoms of fragile X syndrome. Males with the premutation will pass it on to all of their daughters and none of their sons (they pass their Y chromosome on to their sons).

It was resolved by analyzing FMR-1 gene in fragile X families with transmitting males that: transmitting males always have premutations and the daughters of transmitting males inherit about the same number of CGG repeats as found in the fathers. Premutations become unstable after oogenesis in daughters, leading to full mutations with more than hundreds CGG repeats in their offspring. TREATMENT At this time, there is no cure for fragile X syndrome. However, special education, speech and language therapy, occupational therapy and behavioral therapies are helpful in addressing many of the behavioral, and cognitive issues in fragile X syndrome. In addition, medical intervention including medications can be helpful for aggression, anxiety, hyperactivity and poor attention span. Because the impact of fragile X is so varied, it is important to do a careful evaluation of the individuals' abilities and difficulties to tailor a treatment plan to address specific needs. CASE REPORT A case of two brothers, one was--aged 2 years, 9 months and the other was 1 year, 8 months. Both were referred to the hospital for evaluation for developmental delay. At birth, the elder brother weighed 3260 g. Neonatal screening for metabolic diseases and hypothyroidism did not show any abnormalities. He had gross psychomotor retardation: controlled his head at 5 months, sat alone at 12 months and began to walk at 20 months and never spoke any meaningful words. On physical examination Height: 94.5 cm Weight 13.2 kg Head circumference 47.8 cm Head was long, with prominent forehead.

THE SHERMAN PARADOX The Sherman Paradox refers to an anomalous pattern of inheritance found in Fragile X Syndrome. It is also referred to as anticipation or dynamic mutation. Named after Stephanie Sherman, who studied the inheritance patterns of people with this syndrome, observed that the effects of this syndrome seemed to worsen with each succeeding generation. Sherman theorized that the variation in the propensity of premutations to become full mutations may be related to the size of a premutation and the gender of the carrier.

Large ears, incisor was absent and testes were not enlarged. Psychometric testing revealed a development quotient of 38% that of a normal child of the same age. Behavioral abnormalities: hyperactivity, short attention span, poor eye coordination, and excessive withdrawal response to strangers and environment. The younger brother was born at 5th week gestation with a birth weight of 2780g. Psychomotor development was moderately retarded, controlled his head at age 4 months, sat alone at 10 months, could stand up (holding on to furniture at 20 months and could not speak any meaningful words. Physical examination: Normal height and head circumference Hyperactivity Face was square shaped with prominent forehead, everted ears and absent left incisor. DQ was 47% of normal. A third child (female) was also examined. Weight 3462g delivered at term by cesarean section. With the exception of speech, psychomotor development was normal. Normal height and head circumference. Head was square-shaped Intelligence score was 85% that of a normal child. Family medical history revealed presence of mental retardation in one maternal aunt. (IQ was 45. Normal range 77- 124) Other siblings appeared to be intellectually normal with the mothers

IQ=92. While an uncle left highschool to work as a driver. DIAGNOSIS Brothers showed moderate to severe development retardation. Dysmorphic features included long, square-shaped faces, large prominent ears and prominent forehead. Elder brother showed unique behavioral abnormalities and autism. The younger sister also showed borderline mental retardation The three siblings exhibit features of Fragile X Syndrome Submitted by: 1-C2 Group II Jesse Dianne H. Billedo Edmar L. Borigas Shieldon Oliver C. Calayan